Craniosynostosis Definition

1. A syndrome is the association of several clinically recognizable signs and symptoms,

which can occur together in an affected individual. A large number of syndromic

conditions involve the craniofacial region (Gorlin et al, 2001).

2. Abnormal growth pattern of the skull

o skull cannot expand perpendicular to the fused suture

o compensates by growing more in the direction perpendicular to the open

sutures (Virchow’s Law= Virchow's Law, during craniosynostosis, skull growth is

restricted to a plane perpendicular to the affected, prematurely fused suture and is

enhanced in a plane parallel to it.)

o growth pattern provides the necessary space for the growing brain, but results

in an abnormal head shape and facial features

Classification according to mode of inheritance 1. Familial syndrome: Those that occur as part of a characterized Mendelian disorder,

resulting from a single gene defect:

• Autosomal dominant

• Autosomal recessive;

• X-linked dominant

• X-linked recessive

2. Sporadic syndrome: Those arising from structural abnormalities of the chromosomes;

due to teratogenic agents like:

• Teratogen: eg Drugs (alcohol, phenytoin, thalidomide); Physical agents (radiation,

intrauterine mechanical restraint).

• Maternal illness: eg Infections (cytomegalovirus, rubella, syphilis);

• Nutritional

3. Idiopathic

Classification according to clinical features I. Craniosynostoses

• Isolated craniosynostosis 70%

• Syndromic craniosynostosis

a. Apert's syndrome

b. Crouzon's syndrome

c. Pfeiffer syndrome

II. Orofacial clefting syndromes

• Cleft lip and palate

• Pierre-Robin syndrome

III. Brachial arch disorders

• Craniofacial microsomia

• Auriclo-oclu -vertebral syndrom (Goldenhar syndrome)

• Di George's syndrome

• Mandibulofacial dysplasia (Treacher Collins syndrome)

• Oro-facial-digital syndrome

IV. Syndromes affecting bone / cartilage

• Achondroplasia

• Cleido-cranial dysplasia

V. Neural tube defect

• Anencephaly

• Encephaloceles

• Holoproscencephaly

• Hydrocephaly

• Foetal alcohol syndrome (FAS)

• Binder's syndromes (maxillonasal dysplasia)

• Spina bifida

Craniosynostosis

The craniosynostoses are a heterogenous group of disorders characterized by premature

fusion of the cranial sutures. This can occur in isolation or in association with other

anomalies (17%), in a number of well-characterized syndromes.

CRANIAL ANATOMY The newborn infant's skull is composed of bony plates separated by sutures. This

arrangement accommodates transient skull distortion during birth and permits future growth

of the brain, the volume of which quadruples during the first two years of life. There are four

major sutures: the metopic, coronal, sagittal, and lambdoid. Three additional sutures that

contribute to calvarial development are considered minor: the frontonasal,

temporosquamosal, and frontosphenoidal. The sagittal, coronal, and metopic sutures meet at

the anterior of the skull to form the anterior fontanelle, palpable just behind the forehead at

the midline. The posterior fontanelle is formed by the intersection of the sagittal and

lambdoid sutures

Aetiology

Syndromic Craniosynostosis - Genetic mutations

Fibroblast Growth Factor Receptor FGFR 1, 2,3 and TWIST genes

FGFR 2 90% of the syndromic craniosynostoses (Apert, Crouzon, Peiffer)

The mutations can be divided into mutations that lead to;

o Gain of function (in FGFR genes)

o Loss of function (in TWIST genes) 2° effects on ↓FGFR function

Nonsyndromic Craniosynostosis - greatly unknown hypotheses are;

1. Biomechanical factors

Fetal head constraint during pregnancy ↓expression of Indian Hedgehog protein and noggin = factors influencing bone development.

2. Teratogens (Environmental factors)

Maternal smoking

Maternal exposure to amine-containing drugs.

3. Maternal illness (Hormonal factors)

Hyperthyroid induced craniosynostosis - bone matures faster due to high levels of thyroid hormone

4. Genetic factors o In 6 - 11% (bilateral > unilateral) family history

o FGFR3 - 31% of the cases with nonsyndromic coronal synostosis

Diagnosis The diagnosis in cases of syndromic craniosynostosis may require

phenotypic assessment

radiologic (computed tomographic scan)

genotypic (chromosomal and molecular) investigations,

Craniosynostosis may be classified according to the number of involved sutures (single or multiple),

location (sagittal, metopic, unilateral or bilateral coronal, lambdoid, or minor sutures),

as an isolated event (nonsyndromic, simple)

Affect FGFR Genes

Isolated craniosynostosis

Several additional hypotheses regarding the mechanisms underlying premature

closure of cranial sutures in nonsyndromic craniosynostosis have been proposed

1. Systemic factors

I. Craniosynostosis is associated with endocrine abnormalities, such as hyperthyroidism,

and warfarin or valproate use during pregnancy [7,8].

II. There is an increased incidence of isolated craniosynostosis in multiple pregnancies

and in the presence of uterine abnormalities, such as bicornuate uterus, implying that

compression of the fetal skull during pregnancy can contribute to craniosynostosis.

III. Mutations in fibroblast growth factor receptor (FGFR) family [10] may also be found

in patients with nonsyndromic craniosynostosis.

2. Local factors

I. According to Moss's dural hypothesis, abnormal dural attachments exert restrictive

tensile forces that arrest bone growth and lead to premature suture closure

II. alternative theory is that an intrinsic abnormality in the cranial suture cells. produces

early fusion. These cells demonstrate prolonged doubling time and are inhibited by

exposure to osteoblast growth factor

Around 1 : 2,000 children are born with premature fusion of a cranial suture

These cases usually occur sporadically but can also be familial

Fibroblast growth factor receptor (FGFR) and TWIST mutations are the most

commonly associated with Craniosynostosis syndromes.

Most commonly the sagittal; but the coronal, metopic (frontonasal suture) and

lambdoid sutures can also be affected.

The craniofacial features are dependent upon which suture is affected but usually

involve distortion of the skull due to excessive compensatory growth in unaffected regions.

Examples include:

I. True craniocynostosis

A. trigonocephaly (fusion of the metopic suture),

B. Brachycephaly (fusion of the coronal suture and lambdoid suture bilaterally)

C. Dolichocephaly or Scaphocephaly (fusion of the sagittal suture),

D. Plagiocephaly (fusion of coronal and lambdoidal

sutures unilaterally), Lambdoid synostosis was a focus of

interest after the impact of the Back to Sleep campaign

(supine sleeping is better than prone sleep as it has less

effect on cranium, less SID and longer stage 3 Non-REM

and shorter REM which all good) initiated by the American

Academy of Pediatrics in 1994 resulted in an epidemic of

infants with posterior plagiocephaly.

E. Oxycephaly conical or pointed skull, delayed onset bilateral coronal synostosis.

II. Deformational Plagiocephaly

o No fusion of the sutures o Skull changes shape due to extrinsic forces o No bulging of the mastoid o Skull base not affected o Position of the ears is level and displacement of one ear to the front is characteristic

for deformational plagiocephaly.

III. Primary microcephaly

o Absence of growth of the brain → rendering the sutures of the cranial vault useless → the sutures close

o Pansynostosis like image. o Differentiation between these two conditions can be made with a computed

tomography (CT) scan. o

Medical history

Risk factors during pregnancy

Familial rate

Presence of symptoms of elevated intracranial pressure (ICP).

Physical examination

Fundoscopy → papilledema (optic disc swelling 2° to ↑ICP)

Measurement of the head circumference + growth curve

Assess skull deformity

Supplemental analysis

3D CT - gold standard for diagnosing craniosynostosis

Allows for surgical planning and 3D reconstruction/stereolithographic modeling as

required

MRI scans

Genetic testing

Apert's syndrome

Aetiology:

• acrocephalopolysyndactyly type I (typoe II and III are below)

• Autosomal dominant

• It is due to paternal mutation

• Defect in the FGF receptor 2 gene

• Prevalence of the disease (1 in 100,000)

Extraoral sign and symptoms

• Premature fusion of the coronal and frontosphenoidal sutures and the sphenoethmoidal

synchondrosis

Syndactyly of hand and feet (soft tissue and bone). Syndactyly of the hands and feet = Failure of programmed cell death or apoptosis which normally causes separation of the digits → skin, and rarely bone, between the fingers and toes fuses. Especially mediated great toes and thumbs. Fusion of fingers or toes with an equal number on both sides of the body.(symmetrical). It is typical for the middle 3 fingers to be fused together. The thumb and big toe may be broad and malformed. Abnormal shortness is called brachydactyly. Cohen (1984) Classification

I. Type 1: thumb and little finger not fused

II. Tpye 2: only thumb is free

III. Type 3: all fused

• Exophthalmos is always present, largely because of orbital hypoplasia with retruded

supraorbital, infraorbital, and lateral orbital rims.

• The widened cranial base can result in

hypertelorism. orbital dystopia and develop

optic atrophy

• Proptosis

• Midface hypoplasia

• Maxillary hypoplasia

• Class III malocclusion

• Mental retardation more common

than in Crouzon syndrome

• Hearing loss common

• Cardiovascular/genitourinary anomalies w10%

• Cervical spine anomalies (C5 and C6 fusion) common

Intraoral sign and symptoms

• High arched and narrow palate

• CLP

• Bulbous lateral palatal swellings – containing hyaluronic acid

• AOB

• Crowding

• micro and hypodontia

• Delayed eruption

Crouzon's syndrome

• It is due to paternal mutation of fibroblast growth

factor receptor 3 (FGFR3)

• Prevalence 1.6:100,000

• Premature fusion of the coronal and

frontosphenoidal sutures and the sphenoethmoidal

synchondrosis

• Other same as Apert

• Differential diagnosis - Aperts has syndactyly

• Normal IQ and limbs

• Less neuro deficit & less incidence of CP

Pfeiffer syndrome

• Prevalence 1.6:100,000

• It is due to paternal mutation of fibroblast growth

factor receptor 1 (FGFR1)

• Premature fusion of the coronal and frontosphenoidal

sutures and the sphenoethmoidal synchondrosis

• Similar to Apert in addition, the syndrome includes

abnormalities of the hands (such as wide and deviated

thumbs) and feet (such as wide and deviated big toes).

• Skeletal (eg, radiohumeral synostosis of the elbow), central nervous system (CNS; eg,

hydrocephalus), and gastrointestinal abnormalities (eg, imperforate anus) also frequent ly

occur [44].

• The most widely accepted clinical classification of Pfeiffer syndrome was published

by M. Michael Cohen in 1993 by broad thumbs, broad great toes, brachydactyly, and

possibly syndactyly:[3]

I. Type 1, also known as classic Pfeiffer syndrome, includes craniosynostosis and "midface

deficiency." This type is inherited in an autosomal dominant pattern. Most individuals with

type 1 Pfeiffer syndrome have normal intelligence and a normal life span.

II. Type 2 includes a cloverleaf-shaped skull (Kleeblattschädel) due to extensive fusion of

bones, as well as severe proptosis. This type occurs sporadically (i.e., does not appear to be

inherited) and has "a poor prognosis and severe neurological compromise, generally with

early death."

III. Type 3 includes craniosynostosis and severe proptosis. This type occurs sporadically (i.e.,

does not appear to be inherited) and has "a poor prognosis and severe neurological

compromise, generally with early death."

Carpenter syndrome

Carpenter syndrome, also known as acrocephalopolysyndactyly type II

It is associated with mutations in RAB23 (RAS-associated protein), a guanosine triphosphate

hydrolase (GTPase) involved in intracellular membrane trafficking regulation

Similar to Apert but with concurrent coronal, sagittal, and lambdoid craniosynostosis [50] and

hypoplastic mandible and/or maxilla and poludyctyle

Saethre-Chotzen Syndrome

Saethre-Chotzen syndrome, also known as acrocephalosyndactyly type III (MIM #101400), is

an autosomal dominant disorder [51]. Mutations in the TWIST gene, which is located on

chromosome 7p21.1

Patients affected by Saethre-Chotzen syndrome typically have craniosynostosis of coronal,

lambdoid, and/or metopic sutures

The characteristic facial appearance includes a towering (turricephalic) forehead, low-set

hairline, facial asymmetry with septal deviation, and ptosis of the upper eyelids [57,58].

Cutaneous syndactyly, usually partial, frequently occurs and involves the second and third

fingers and/or the third and fourth toes [44]. Most patients have normal intelligence.

Treatment considerations in craniosynostosis syndromes

Vargervik et al 2012

The interdisciplinary teams can be comprised of professionals from the fol-lowing

disciplines:

Craniofacial surgery,

Hand surgery,

Neurosurgery,

Ophthalmology,

Oral and maxillofacial surgery,

Orthodontics,

Otolaryngology,

Pediatrics

Pediatric dentistry,

Prosthodontics,

Psychology,

Radiology,

Social work,

Anesthesiology,

Genetics,

Intensive care,

Nursing,

Speech and language pathology.

I. Airway and feeding

Obstructive sleep apnea is common due to:

• Midface deficiency,

• Choanal stenosis or atresia,

• Long thick velum,

• Laryngotracheal anomalies,

• Central apneas

Management

• As lymphoid tissue reaches its peak size tonsillectomy or adenoidectomy may not be

indicated.

• Nasopharyngeal tubes

• Continuous positive airway pressure

• Tracheostomy are sometimes required.

• Midfacial advancement may prove helpful for children and adolescents.

• Assessment for central apnea begins in infancy; reassessment frequency is determined by

diagnosis and individual features.

II. Central nervous system

Increased intracranial pressure (ICP) is a concern whenever

sutures fuse prematurely

Signs and symptoms of increased ICP include

• a bulging fontanelle

• radiographic beaten copper skull appearance

• headaches,

• nausea

• vomiting,

• irritability;

• diagnosis can be challenging, especially in the very young

Management

• a ventriculoperitoneal shunt,

• endoscopic third ventriculostomy,

• early/repeat cranial decompression.

III. Other systems

• Exophthalmos increases risk for corneal abrasion, exposure keratitis, and globe trauma.

Ocular lubrication, tarsorrhaphy, or early fronto-orbital advancement are strategies to protect

the globes.

• Patients require regular evaluation for middle ear disorders and hearing loss, which are

common.

• Timing of cleft palate repair depends on speech acquisition; it may be delayed relative to

routine cleft management.

• Dental development should be monitored by a pediatric dentist and an orthodontist.

• Limb anomalies are managed by pediatric orthopedists.

• Visceral anomalies are managed by the appropriate specialists.

• Genetic evaluation and counselling are crucial.

• The potential psychosocial and educational impact of these conditions necessitates ongoing

monitoring by a trained psychiatrist or psychologist.

IV. Dental, orthodontic and craniofacial surgery

The roles of orthodontist are:

Coordinate dental care across primary and secondary care as needed

Review the development and eruption of the dentition and establishment of the occlusion

from birth onwards

Provide or oversee orthodontic treatment to: align the dentition, create interdental space for

osteotomies and prepare for orthognathic surgery

A staged approach

1. 1st -2nd year of life:

Baseline diagnostic records (eg, full head CT scans; cephalograms; intraoral, facial, and head

photographs)

Fronto-orbital advancement, involving fused suture release,

anterior vault and orbital expansion,

forehead and orbital bandeau reshaping, is typically performed in the first year of life.

Posterior vault expansion

Caries risk assessment

Anticipatory guidance or counseling (oral hygiene, dietary, injury prevention, non-nutritive

habits)

Fluoride supplementation assessment

Dental prophylaxis and topical fluoride

Monitor craniofacial growth and development, including the deciduous dentition

2. Mixed dentition:

Baseline diagnostic records (eg, full head CT scans; cephalograms; intraoral, facial, and head

photographs)

Midfacial advancement to address orbital and zygomatic deformities is performed in early

childhood (after 5e7 years of age), at which time the cranial vault and orbits approximate

90% of adult size. Midfacial advancement techniques include:

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012_11_29_FORREST_205023_SDC2.flv.html

a. Monobloc advancement, this is indicated only if at least 3 of the following are

present:

increased ICP

risk of ocular damage

respiratory problem

speech

aesthetic

occlusion

b. facial bipartition,

The facial bipartition. Moving the orbits into the correct position results in a transverse expansion

of upper dental arch and creates midline diastema the size of which is determined by the amount

of orbital movement and the point of rotation.

For the FFA mortality rates as high as 4.5% have been reported mainly due to CS fluid leakage,

bleeding or infection.

c. subcranial Le Fort III osteotomy; a technique is selected based on the individual

patient’s situation.

Caries risk assessment

Periodontal disease assessment

Anticipatory guidance or counseling (oral hygiene, dietary, injury prevention, nonnutritive

habits)

Fluoride supplementation assessment

Dental prophylaxis and topical fluoride

Evaluation of molar positions before surgical procedures and planning with surgeon for the

best approach to prevent damage to unerupted teeth

Pit and fissure sealant assessment

Phase 1 orthodontic treatment

Provide active eruption guidance for permanent teeth that are severely delayed Retention

between active orthodontic treatment phases

3. 12-21 years:

Baseline diagnostic records (eg, full head CT scans; cephalograms; intraoral, facial, and head

photographs)

Further midfacial advancement and onlay grafting is nearly always required at skeletal

maturity

Orthodontic decompensation and orthognathic surgery are then performed.

Esthetic nasal and soft tissue surgery are best delayed until after orthognathic surgery.

Caries risk assessment

Periodontal disease assessment

Fluoride supplementation assessment

Dental prophylaxis and topical fluoride

Pit and fissure sealant assessment

Management of dental impactions with surgical exposure and orthodontic assisted eruption

Phase 2 orthodontic treatment